HIS25 Tolerance And Autoimmunity Flashcards
Pathogenesis of Autoimmunity
- immune response directed against self
- may not cause disease (i.e. asymptomatic but carry AutoAb)
- factors:
—> Familial
—> Genetic
—> Hormonal
—> Environmental
Central and Peripheral tolerance to self Ag
Central tolerance:
Immature lymphocytes specific for self Ag may encounter these Ags (Cell bound MHC) in Central lymphoid organ (BM / Thymus)
—> ***Clonal deletion: deleted before maturation and released into circulation
Peripheral tolerance:
Mature self-reactive lymphocytes encounter self Ag (Soluble MHC) in Peripheral lymphoid tissue
—> ***Anergy / Suppression / Deletion
Mechanism of Central tolerance
Clonal deletion
—> auto-reactive cells deleted early in development within primary organs
E.g. Thymic epithelial cells possess AIRE (autoimmune regulator) gene
—> regulator of gene transcription that stimulates Thymic expression of many self-Ag which are largely restricted to peripheral tissue
—> expression of Tissue-restricted antigens (TRAs)
—> if immature T cell strongly self-reactive to TRA
—> Apoptosis (negatively selected)
Clinical relevance of Central tolerance
Patients have problem with AIRE gene —> cannot express TRA for clonal selection —> defective clonal deletion —> failure of central tolerance —> autoimmunity development
Mechanisms of Peripheral tolerance
- Clonal anergy: mature lymphocytes leave primary organs but become functionally unresponsive (tolerised) to self molecules
—> self reactive T cells cannot be activated in quiescent phase (no immune stimulation)
—> can bind to self-Ag but do ***not have Co-stimulatory signals (only present with appropriate immune activation context) to become activated
—> Clonal anergy (self-tolerance) - Activation-induced cell death
- negative feedback to T cells after a while of activation (e.g. CTLA4 signaling)
—> apoptosis
—> prevent excessive activation - Sequestrated antigen
- Immunologically privileged sites / anatomically isolated (e.g. eyes, testes)
- precluded from contact with lymphocytes
- lack of Ag presentation - Treg cells (special Th cells): CD4+, CD25+
—> production of suppressive cytokines TGFβ and IL-10
—> actively suppressing autoreactive T cells
—> maintain peripheral self tolerance
***Breakdown of self tolerance
- Monogenic conditions (關T cell事):
- Defective Central tolerance
Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED)
- **disruption of AIRE gene —> **defective clonal deletion —> results in development of range of autoimmune diseases:
—> hypoparathyroidism
—> adrenal insufficiency (primary adrenocortical failure)
—> chronic mucocutaneous candidiasis - Defective Peripheral tolerance
IPEX (Immune dysfunction, Polyendocrinopathy, Enteropathy, X-linked)
—> **deletion in transcriptional regulator FoXP3
—> loss-of-function of this gene
—> **lack of Treg cells
—> syndrome of lymphoproliferative, autoimmune, allergic disorders identified in human and mice
More common
2. Induction of MHC class II Ag on non-APC (e.g. ***thyroid epithelial cells) by IFNγ
—> enhance Ag presentation to T cells
—> decrease threshold of developing autoimmune response
—> if infection —> prone to autoimmune disease
- Cross-reacting microbial Ag which has peptide sequences in common with self Ag
- e.g. after rheumatic fever by Strept pyogenes
—> immune response against Strept cross reactive with endothelium of heart
—> long term inflammation
—> rheumatic heart disease - Release of sequestrated Ag
- sympathetic ophthalmia (traumatised eyes —> eye Ag released into circulation —> activated T cells —> reach intact eye as well —> inflammation of both eyes)
- after vasectomy
Role of infections in autoimmunity development
Infection —>
- Activation of APC carrying self Ag
—> APC ***express Co-stimulatory signals e.g. B7
—> Presentation of self-Ag to Self-reactive T cell (originally anergy due to lack of co-stimulation)
—> Activation of Self-reactive T cell
—> Autoimmunity
2. ***Molecular mimicry —> Activation of APC with microbial Ag —> Self-reactive T cell recognise microbial peptide —> Activation of Self-reactive T cell —> Autoimmunity
T helper cells
Th1 balances Th2 Th1: - Cell-mediated immunity - IFNγ - Intracellular pathogens (virus, bacteria) - Inflammation - Drives autoimmunity - NKs, Neutrophils
Th2:
- Ab-mediated immunity + Allergy, Asthma (produce IgE by B cell —> bound on Mast cells)
- IL-4
- Extracellular parasites
- Antibodies
Treg balances T17 Treg: - CD4+, CD25+, FoXP3+ - TGFβ + IL-10 - Immune tolerance - Immune suppression - Immune response regulation
Th17:
- Cell-mediated immunity
- Extracellular bacteria (e.g. skin, intestinal lining) + Fungi
- Autoimmunity
- Inflammation
Treg cells
- Thymus-derived
- CD4+, CD25+, FoXP3+
- Mediate self tolerance + Prevent autoimmune disease
- Deficiency of FoXP3+ cells: Defective peripheral tolerance —> IPEX
Function:
—> production of suppressive cytokines **TGFβ + **IL-10
—> actively ***suppressing autoreactive T cells
—> maintain peripheral self tolerance
Th1 and Th2 CD4+ T cells in pathogenesis of autoimmune diseases
Functional subsets of Th:
- Th1, Th2, Th0 (naive T cell)
Th1:
- IL-2, IFNγ, TNF, lymphotoxin (LT)
- intracellular pathogens
- support **Macrophage activation, **Delayed-type hypersensitivity response (e.g. Granulomatous inflammation)
Th2:
- IL-4, IL-5, IL-6, IL-10, IL-13
- provide help for B cell activation, **Ab production, **Class switch to IgG1, IgE isotypes
Th0 (naive T cells):
- produce cytokines of both Th1, Th2
- precursors of Th1, Th2
Reciprocal regulation occurs between Th1 and Th2
- IL-12 (by APC) drives differentiation of Th1
—> IL-12 induce IFNγ
—> ***IFNγ inhibits differentiation and effector functions of Th2 —> dominant Th1 response
- ***IL-4 directs development of Th2
—> products of Th2
—> IL-4, IL-10, IL-13 inhibits Th1 proliferation
—> oppose effects of IFNγ on macrophages
Etiology of autoimmune diseases
Usually multifactorial, different factors together contribute to autoimmune diseases
- Genetic factors
- **Familial clustering: disease prevalence within families where there is affected individual, compared with prevalence in general population
- **Twins studies: prevalence of disease in pairs of identical twins is higher compared to non-identical twins (i.e. concordance in identical twins higher)
—> prove that shared genetic causes > shared environmental causes
- NO clear Mendelian inheritance / Monogenic (APECED, IPEX uncommon)
- Usually **multiple genes involved - both MHC and non-MHC genes
- Relatively **low penetrance of each gene (each gene contribute little)
- ***Genetic heterogeneity i.e. different genes and gene combinations can lead to same disease - Hormonal factors
- many autoimmune diseases have ***sex preponderance (e.g. SLE F:M ~ 9:1, also more common in reproductive age of women)
- animal studies:
—> administration of male sex hormones, castration to female lupus mice
—> retard development of lupus disease - Environment factors (mainly infective)
- **geographical clustering not explained by genetic variation is strong evidence of environmental effects
—> **MS, IDDM, Autoimmune thyroiditis
—> but not in SLE, RA
- infection with **rubella (congenital), **enterovirus —> associated with increased risk of IDDM
- other envionmental factors:
—> Drugs: **Hydralazine, Penicillamine: drug-induced lupus; ***Methyldopa: haemolytic anaemia
—> Dietary iodine implicated in development/exacerbation of autoimmune thyroiditis
—> Sun exposure exacerbate SLE
MHC genes
Close association between HLA allotypes and susceptibility to autoimmune disease (∵ MHC directly involved in Ag presentation between APC and T cell)
- esp. HLA Class II (encodes for MHC Class II)
—> HLA-DR4 and RA
—> HLA-DR3/4 and Insulin-dependent DM
(Lecture 13: HLA-DR gene is polymorphic)
Classification of Autoimmune diseases
Organ specific
- Endocrine organs (usually) (Addison’s disease, AI thyroiditis)
- Renal (anti-glomerular basement membrane GBM disease)
- Haematological (AI haemolytic anaemia)
- Muscles (Myasthenia gravis)
- Stomach (Pernicious anaemia)
- Pancreas (IDDM)
Lesions:
***Ag in a particular organ is targeted for immunological attack
Mechanisms of diseases:
- **AutoAb interact with **cell surface components (e.g. MG: AutoAb to ACh receptor)
- ***Sensitisation of T cells —> tissue damage (e.g. CD4+ T cells + Recruited macrophages —> Hashimoto’s thyroiditis)
Non-organ specific
Multi-system disorders
- Rheumatic diseases (SLE, RA)
- Vasculitis (Wegener’s granulomatosus, Polyarteritis nodosa)
Lesions:
***Immune complexes deposit systemically particular in kidneys, joint, skin
Mechanisms not always clear
1. Cytokines produced by T cells and macrophage (e.g. RA, rheumatoid factor has little role)
2. ***Immune complex formation (e.g. SLE, anti-dsDNA forms immune complex with dsDNA —> deposit in kidney, other tissues)
3. AutoAb against widely distributed Ag:
—> e.g. nuclei (anti-nuclear Ab), mitochondria (anti-mitochondrial Ab)
—> not necessarily pathogenic (but may be marker of process, used in diagnosis)
—> useful in patient management (diagnosis, monitoring) (e.g. SLE)
Other classifications: Involved systems (kidney, skin etc.), Pathogenesis (AutoAb, immune complex, T cells)
Clinical features of Autoimmune diseases
Variable (depend on target organ involved and nature of immune response)
- Thyroid:
Hashimoto’s disease
- gland size ↑
- function usually normal, later Hypothyroidism, occasionally Hyperthyroidism (transient Thyrotoxicosis)
Grave’s disease
- gland size ↑ (Anti-TSH receptor Ab)
- Hyperthyroidism
Primary myxedema
- gland size ↓
- function below normal
- Autoimmune cytopenia (organ-specific, but can also be part of non-organ specific process e.g. SLE)
- haemolytic anaemia
- autoimmune thrombocytopenia
- autoimmune neutropenia - Goodpasture’s syndrome
- anti-GBM Ab
- Nephritis +/- renal failure
- Pulmonary haemorrhage (as GBM also present in alveoli) - Myasthenia gravis
- anti-ACh receptor Ab
- impair NMJ transmission - muscle weakness - SLE (non-organ specific)
- skin rash, arthritis, nephritis, cytopenia, serositis, cerebritis (different patients have different disease manifestations)
Laboratory investigation of Autoimmune diseases
- Screening
- Monitoring
- Prognosis
